Starvation Signals Control Intestinal Inflammation in Mice

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Intestinal inflammation in mice can be dampened by subjecting them briefly to a diet restricted in amino acids, the building blocks of proteins, research published in Nature shows.

The findings, made by Bali Pulendran and colleagues at Emory University, highlight an ancient connection between cellular mechanisms to sense nutrient availability and control of inflammation. They also suggest a low protein diet -- or drugs that mimic its effects on immune cells -- could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

This protective effect was shown to be mediated by a molecule known as GCN2, which is highly conserved from yeasts to man, and which is a critical sensor of amino acid starvation in cells. The finding grew out of the Emory team’s earlier discovery that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“We reasoned the intestine would be a site where the immune system is faced with dynamic changes in nutrient bioavailability,” says senior author Bali Pulendran, PhD. “So we wondered whether the amino acid sensing pathway involving GCN2 would impact immune homeostasis in the gut.”

Pulendran is Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine, Emory Vaccine Center and Yerkes National Primate Research Center. The co-first authors of the paper are postdoctoral fellows Rajesh Ravindran, PhD, and Jens Loebbermann, PhD. Co-authors on the paper include Randal Kaufman, PhD, at the Sanford Burnham Prebys Medical Discovery Institute and Jennifer Martinez, PhD, at the National Institute of Environmental Health Sciences.

The team discovered that mice lacking GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. In the absence of irritants, the intestines in mice lacking GCN2 looked normal.

Mice fed a low protein diet (2 percent, compared to 16 percent in a standard diet) or a diet lacking only the amino acid leucine were protected from signs of colitis, such as weight loss and bloody diarrhea. Mice lacking GCN2 were not protected from colitis when fed a low protein diet, which demonstrates that GCN2 is necessary for the protective effect.

The results could have implications for treatment of inflammatory bowel diseases and autoimmune diseases, such as rheumatoid arthritis and psoriasis. The researchers showed that responses of Th17 immune cells, which are important in several autoimmune diseases, are controlled by GCN2.

“It is well known the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” Pulendran says, “It is interesting to ponder the evolutionary pressures that might have resulted in the coupling of this ancient amino acid starvation pathway with control of inflammation.” Perhaps this coupling evolved as a sort of negative feedback mechanism to limit inflammation, by sensing depletion of amino acids that might occur in cells during the repair and regeneration of tissues, in response to cell death during inflammation.”

Pulendran cautions more research is needed before applying the findings to human inflammatory bowel diseases. For instance, a low-protein diet is not advisable for long periods, although a low-protein diet is sometimes recommended for people with kidney disease to postpone the need for dialysis. The duration or extent of a low-protein diet needed to have the desired effect on intestinal inflammation in humans is not clear.

The research was supported by the National Institute of Allergy and Infectious Diseases (R37 AI048638, U19 AI090023, U19 AI057266), the National Institute of Diabetes and Digestive and Kidney Diseases (R37 DK057665), the NIH Director’s Office of Research Infrastructure Programs (Primate centers: P51OD1132) and the Bill & Melinda Gates Foundation.

For eight decades, the Yerkes National Primate Research Center, Emory University, has been dedicated to conducting essential basic science and translational research to advance scientific understanding and to improve the health and well-being of humans and nonhuman primates. Today, the center, as one of only seven National Institutes of Health–funded national primate research centers, provides leadership, training and resources to foster scientific creativity, collaboration and discoveries. Yerkes-based research is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate quality animal care.

Within the fields of microbiology and immunology, neurologic diseases, neuropharmacology, behavioral, cognitive and developmental neuroscience, and psychiatric disorders, the center’s research programs are seeking ways to: develop vaccines for infectious and noninfectious diseases; understand the basic neurobiology and genetics of social behavior and develop new treatment strategies for improving social functioning in ASD and schizophrenia; interpret brain activity through imaging; increase understanding of progressive illnesses such as Alzheimer’s and Parkinson’s diseases; unlock the secrets of memory; treat drug addiction; determine how the interaction between genetics and society shape who we are; and advance knowledge about the evolutionary links between biology and behavior.

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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.